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研究生:黃建源
研究生(外文):Jian-Yuan Huang
論文名稱:阻斷眼眶前額葉多巴胺D2受器無法消除阿托莫西汀在自發性高血壓大鼠於注意力轉換作業中之行為療效
論文名稱(外文):Blockage of dopamine D2 receptor in orbitofrontal cortex fails to abolish the performance improving effects of atomoxetine on the spontaneusly hypertensive rat in an attentional set-shifting task
指導教授:李季湜李季湜引用關係
指導教授(外文):Jay-Shake Li
口試委員:蕭世朗何應瑞
口試委員(外文):Sigmund HsiaocYing-Jui Ho
口試日期:2013-06-18
學位類別:碩士
校院名稱:國立中正大學
系所名稱:心理學研究所
學門:社會及行為科學學門
學類:心理學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:47
中文關鍵詞:注意力缺陷過動症青少年抑制功能思鋭利他能
外文關鍵詞:ADHDSHRAdolescentInhibitory functionStratteraRitalin
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注意力缺陷過動症(attention-deficit hyperactivity disorder, ADHD) 主要症狀包含注意力不足、過動及衝動控制困難。阿托莫西汀(atomoxetine, ATX) 是目前臨床新一代治療 ADHD 的非中樞神經興奮劑,為選擇性正腎上腺素(norepinephrine, NE)的再回收抑制劑,主要會提高正腎上腺素突觸間的濃度。特別的是,過去研究發現 ATX 在前額葉(prefrontal cortex, PFC)能夠同時提高多巴胺(dopamine)的濃度,類似於第一線藥物 methylphenidate 的作用。然而,目前研究尚無法釐清 ATX 藥物治療的神經機制;ATX 可能直接透過 NE 產生療效,也有可能是間接透過多巴胺系統來作用。本研究嘗試以四至六週大的自發性高血壓大鼠(spontaneously hypertension rat, SHR)作為 ADHD 動物模式,檢驗周邊或中樞給予 ATX 能否改善 SHR 在注意力轉換作業(attentional set-shifting task, ASST)的行為表現,以及在眼眶前額葉注射多巴胺 D2 受器拮抗劑haloperidol 能否阻斷 ATX 的治療效果。實驗一,在測驗當天給予大鼠 ATX (0.3 mg/kg) 30 分鐘之後,讓大鼠進行注意力轉換作業的學習,以確認周邊給予 ATX 的治療效果。其中,在反向學習(reversal learning)階段,大鼠必須學會先抑制之前已習得的反應,並且反轉該行為策略,才能成功獲得酬賞物,屬於較困難的學習階段。實驗二,在測驗當天直接於雙側的眼眶前額葉注射 ATX (0.1 μg/0.5 μl/side),以確認眼眶前額葉是否為 ATX 改善 SHR 在注意力轉換作業上表現的關鍵腦區。實驗三,在測驗當天腹腔注射 ATX(0.3 mg/kg) 30 分鐘之後,分別於雙側的眼眶前額葉注射多巴胺 D2 受器選擇性拮抗劑 haloperidol (0.5 μg/0,4μl/side),以檢驗多巴胺 D2 拮抗劑能否阻斷 ATX 的治療效果。結果發現,周邊給予 ATX 能夠有效改善 SHR 在注意力轉換作業中反向學習的表現;而眼眶前額葉是 ATX 作用的關鍵腦區;此外,即使阻斷眼眶前額葉的多巴胺 D2 受器的作用也無法影響 ATX 的治療效果。因此,本研究推測眼眶前額葉是 ATX 改善SHR 在注意力轉換作業上反向學習的表現,並非透過眼眶前額葉的多巴胺 D2 受器作用所致。

Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder. The symptoms include inattention, hyperactivity and impulsivity. Atomoxetine (ATX) is a selective norepinephrine reuptake inhibitor which served as a non-psychostimulant drug for the treatment for ADHD. Previous studies found that ATX increases not only norepinephrine levels but also dopamine levels in prefrontal cortex. The effect of ATX on the dopamine system is similar to methylphenidate, the first-line treatment for ADHD. However, the neural mechanism of ATX treatment of ADHD is still unclear. In experiment 1, we examined the effect of systemic ATX on juvenile SHR and Wistar control in attentional set-shifting task. During reversal learning phase, rats received reinforcements only if they successfully inhibited impulsive responses and learned reversed rules. In experiment 2, we further investigated the effect of central ATX (0.1 μg/0.5 μl/side) in the orbitofrontal cortex (OFC) on juvenile SHR. In order to examine whether the behavior improvement of ATX is indirectly through the dopamine D2 receptors, we applied intra-OFC infusion of haloperidol (0.5 μg/0.4 μl/side) in experiment 3. The results showed that ATX injection through intraperitoneal as well as intra-OFC can remove the reversal learning deficits of SHR. Central infusion of haloperidol in OFC failed to abolish the beneficial effects of ATX. We suggested that the OFC dopamine system might not be involved in the treatment effects of ATX on ADHD.
目錄
摘要................................................................................................................................. i
Abstract....................................................................................................................... iii
第一章 緒論............................................................................................................ 1
1.1 ADHD與抑制功能缺失理論....................................................................... 1
1.2 多巴胺缺失理論與藥物治療.................................................................... 4
1.3 Atomoxetine作用機制............................................................................. 7
1.4 實驗目的.................................................................................................... 9
第二章 材料及方法.............................................................................................. 12
2.1 受試動物.................................................................................................. 12
2.2 藥物.......................................................................................................... 12
2.3 實驗設備.................................................................................................. 13
2.4 實驗設計及分組...................................................................................... 13
2.5 ASST作業流程......................................................................................... 14
2.6 手術程序.................................................................................................. 16
2.7 染色與定位.............................................................................................. 16
2.8 分析方法.................................................................................................. 16
第三章 結果.......................................................................................................... 18
3.1 實驗一:急性(acute)atomoxetine治療之影響................................. 18
3.2 實驗二:atomoxetine在眼眶前額葉的作用....................................... 20
3.3 實驗三:多巴胺D2受器阻斷效果........................................................ 21
第四章 討論.......................................................................................................... 24
4.1 實驗結果總結.............................................................................................. 24
4.2 正腎上腺素與反向學習.............................................................................. 24
4.3 多巴胺與反向學習...................................................................................... 25
vi
4.4 眼眶前額葉在反向學習上扮演的角色...................................................... 26
4.5 Atomoxetine劑量與作用時效................................................................... 27
4.6 不同行為實驗條件之比較.......................................................................... 28
4.7 與臨床研究之比較...................................................................................... 30
參考文獻...................................................................................................................... 33
附錄.............................................................................................................................. 43
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